Sertraline.

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Zoloft or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Zoloft is not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD).

 

Sertraline (sertraline hydrochloride) is a selective serotonin reuptake inhibitor (SSRI) for oral administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following chemical name: (1 S-cis)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthalenamine hydrochloride. The empirical formula C17H17NCl2•HCl is represented by the following structural formula:

 

Use:
SSRI. Depression: Patients > 18 years of age: Initially, 50 mg once daily; increase dosage gradually, if needed, at 1-week intervals. Maximum: 200 mg/day. Maintenance: lowest effective dose.

Panic disorder: 25 mg once daily and increase, if necessary, by 50 mg increments at intervals of no less than 1 week, to a maximum of 200 mg/day.

Obsessive-compulsive disorder (OCD): Initially, 50 mg/day. Thereafter, increase the dosage, if necessary, by 50 mg increments, over several weeks or months, to a maximum of 200 mg/day.

Sertraline’s effectiveness for more than 12 weeks of therapy in panic disorder and OCD not yet established.

Pharmacology

Antidepressant

The antidepressant effect of sertraline is presumed to be linked to its ability to inhibit the neuronal reuptake of serotonin. It has only very weak effects on norepinephrine and dopamine neuronal reuptake. At clinical doses, sertraline blocks the uptake of serotonin into human platelets.

Like most clinically effective antidepressants, sertraline downregulates brain norepinephrine and serotonin receptors in animals. In receptor binding studies, sertraline has no significant affinity for adrenergic (alpha(1), alpha(2) and beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5-HT1A, 5-HT1B, 5-HT2) or benzodiazepine binding sites.

In placebo-controlled studies in normal volunteers, sertraline did not cause sedation and did not interfere with psychomotor performance.

Pharmacokinetics:
Following multiple oral once-daily doses of 200 mg, the mean peak plasma concentration (C(max)) of sertraline is 0.19 mcg/mL occurring between 6 to 8 hours post-dose. The area under the plasma concentration time is 2.8 mg hr/L. For desmethylsertraline, C(max) is 0.14 mcg/mL, the half-life 65 hours and the area under the curve 2.3 mg hr/L. Following single or multiple oral once-daily doses of 50 to 400 mg/day the average terminal elimination half-life is approximately 26 hours. Linear dose proportionality has been demonstrated over the clinical dose range of 50 to 200 mg/day.

Food appears to increase the bioavailability by about 40%: it is recommended that sertraline be administered with meals.

Sertraline is extensively metabolized to N-desmethylsertraline, which shows negligible pharmacological activity. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation and glucuronide conjugation. Biliary excretion of metabolites is significant.

Approximately 98% of sertraline is plasma protein bound. The interactions between sertraline and other highly protein bound drugs have not been fully evaluated (see Precautions).

The pharmacokinetics of sertraline itself appear to be similar in young and elderly subjects. Plasma levels of N-desmethylsertraline show a 3-fold elevation in the elderly following multiple dosing, however, the clinical significance of this observation is not known.

Liver and Renal Disease:
The pharmacokinetics of sertraline in patients with significant hepatic or renal dysfunction have not been determined.

Precautions

Activation of Mania/Hypomania:
During clinical testing in depressed patients, hypomania or mania occurred in approximately 0.6% of sertraline-treated patients. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed antidepressants.

Seizure:
Sertraline has not been evaluated in patients with seizure disorders. These patients were excluded from clinical studies during the product’s premarket testing. Accordingly, sertraline should be introduced with care in epileptic patients.

Suicide:
The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Therefore, high risk patients should be closely supervised throughout therapy and consideration should be given to the possible need for hospitalization. In order to minimize the opportunity for overdosage, prescriptions for sertraline should be written for the smallest quantity of drug consistent with good patient management.

Occupational Hazards:
Any psychoactive drug may impair judgment, thinking, or motor skills, and patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that the drug treatment does not affect them adversely.

Patients with Concomitant Illness:
General:
Clinical experience with sertraline in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using sertraline in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

Cardiac Disease:
Sertraline has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease.

The electrocardiograms of 598 patients who received sertraline were compared in a blinded fashion to the electrocardiograms of 244 placebo patients and 206 amitriptyline patients. The data indicate that sertraline is not associated with the development of significant ECG abnormalities.

Effect on Blood Pressure:
The frequency of clinically noticeable changes (+/-15 to 20 mm Hg) in blood pressure in placebo controlled studies was similar for patients being treated with sertraline or placebo (see Table I).

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Table I

Percentage of Patients with Noticeable Changes in Blood Pressure

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                 Change                      Numbers and % of Patients

               Relative to   Numbers Tested     with Specified Change

Parameter       Baseline   Sertraline Placebo  Sertraline  Placebo

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Standing        increase      703       358    13    1.8%   3  0.8%

 Systolic BP    decrease                       31    4.4%  16  4.5%

Standing        increase      703       358    20    2.8%  13  3.6%

 Diastolic BP   decrease                       28    4.0%  12  3.4%

Supine          increase      706       362    15    2.1%   6  1.7%

 Systolic BP    decrease                       19    2.7%   7  1.9%

Supine          increase      706       362    16    2.3%   7  1.9%

 Diastolic BP   decrease                       18    2.5%   4  1.1%

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Hepatic Dysfunction:
Sertraline is extensively metabolized by the liver. The pharmacokinetics and therapeutic efficacy of sertraline have not been studied in patients with significant hepatic dysfunction. Accordingly, it should be used with caution in such patients.

Renal Dysfunction:
Sertraline is extensively metabolized and excretion of unchanged drug in the urine is a minor route of elimination. The pharmacokinetics of sertraline have not been studied in patients with renal impairment and, until adequate numbers of patients with mild, moderate or severe renal impairment have been evaluated during chronic treatment with sertraline, it should be used with caution in such patients.

Carcinogenesis:
In carcinogenicity studies in CD-1 mice, sertraline at doses up to 40 mg/kg produces a dose related increase in the incidence of liver adenomas in male mice. Liver adenomas have a very variable rate of spontaneous occurrence in the CD-1 mouse. The clinical significance of these findings is unknown.

Pregnancy and Lactation:
The safety of sertraline during pregnancy and lactation has not been established and therefore, it should not be used in women of childbearing potential or nursing mothers, unless, in the opinion of the physician, the potential benefits to the patient outweigh the possible hazards to the fetus.

Labor and Delivery:
The effect of sertraline on labor and delivery in humans is unknown.

Children:
The safety and effectiveness of sertraline in children below the age of 18 have not been established.

Geriatrics:
462 elderly patients (>=65 years) have participated in multiple dose therapeutic studies with sertraline. The pattern of adverse reactions in the elderly was comparable to that in younger patients.

Drug Interactions:
Co-Administration of Drugs Highly Bound to Plasma Proteins:
Because sertraline is highly bound to plasma proteins, the co-administration of other highly bound drugs such as warfarin or digitoxin may cause a shift in plasma concentrations potentially resulting in adverse effects. At this time, the effect of sertraline on the anticoagulant activity of warfarin is unknown. Accordingly, prothrombin time should be carefully monitored when sertraline therapy is initiated or discontinued. Conversely, adverse effects may result from displacement of protein bound sertraline by other tightly bound drugs.

CNS Active Drugs:
The risk of using sertraline in combination with other CNS active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of sertraline and such drugs is required.

Co-administration with tryptophan may lead to a high incidence of serotonin-associated side effects. There is no experience with the concomitant use of sertraline and tryptophan in depressed patients.

In placebo-controlled trials in normal volunteers, the combined administration of lithium and sertraline did not alter the pharmacokinetics of sertraline. There is, however, no clinical experience with sertraline in lithium treated patients. Therefore, it is recommended that plasma lithium levels be monitored following initiation of sertraline therapy, so that appropriate adjustments to the lithium dose may be made if necessary. Co-administration with lithium may lead to a high incidence of serotonin-associated side effects.

Electroconvulsive Therapy:
There are no clinical studies with the combined use of electroconvulsive therapy (ECT) and sertraline.

Alcohol:
Although sertraline did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of sertraline and alcohol in depressed patients has not been studied and is not recommended.

Hypoglycemic Drugs:
There are no controlled clinical trials with sertraline in diabetic patients treated with insulin or oral hypoglycemic drugs.

In a placebo-controlled trial in normal volunteers, the administration of sertraline for 22 days (dose was 200 mg/day for the final 13 days), caused a statistically significant 16% decrease in the clearance of tolbutamide following an i.v. dose of 1000 mg.

Hypoglycemia requiring dextrose infusion was observed in one patient treated with sertraline, glibenclamide, haloperidol, bisacodyl, ASA and flucloxacillin. The causal relationship to sertraline treatment was not firmly established. Nevertheless, close monitoring of glycemia in patients treated with sertraline and oral hypoglycemic drugs or insulin is recommended.

Beta Blockers:
There is no experience with the use of sertraline in hypertensive patients controlled by beta-blockers. In a placebo-controlled crossover study in normal volunteers, the effect of sertraline on the beta-adrenergic blocking activity of atenolol was assessed. The mean CD25’s (the doses of isoproterenol required to increase heart rate by 25 bpm, the chronotropic dose 25 or CD25) and the average decreases in heart rate seen with atenolol during exercise test were not statistically different in the sertraline versus the placebo group. These data suggest that sertraline does not alter the beta-blocking action of atenolol.

Cimetidine:
In a placebo-controlled crossover study in normal volunteers, the potential of cimetidine to alter the disposition of a single 100 mg dose of sertraline was assessed. The mean sertraline C(max) and AUC were significantly higher in the cimetidine-treated group, as were the mean desmethylsertraline T(max) and AUC. These data suggest that concomitant administration of cimetidine may inhibit the metabolism of sertraline and its metabolite, desmethylsertraline, and may result in a decrease in the clearance and first pass metabolism of sertraline, with a possible increase in drug-related side effects.

Microsomal Enzyme Induction:
Sertraline was shown to induce hepatic enzymes as determined by the decrease of the antipyrine half-life. This degree of induction reflects a clinically insignificant change in hepatic metabolism.

Overdose

Symptoms and Treatment:
Human Experience:
There have been 3 cases of sertraline overdosage (approximately 4 to 10 times the maximum recommended daily dose). These 3 patients recovered completely without the need for specific therapy.

Management of Overdoses:
Establish and maintain an airway, insure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage, and should be considered in treating overdose.

Cardiac and vital signs monitoring are recommended along with general symptomatic and supportive measures.

There are no specific antidotes for sertraline.

Due to the large volume of distribution of sertraline, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit.

In managing overdose, the possibility of multiple drug involvement must be considered.

Dosage

The administration should be initiated at 50 mg daily and increased gradually if needed, noting carefully the clinical response and any evidence of intolerance. It should be kept in mind that there may be a lag in therapeutic response. Increasing the dosage rapidly does not normally shorten this latent period and may increase the incidence of side effects.

Initial Treatment:
As no clear dose-response relationship has been demonstrated, a dose of 50 mg/day is recommended as the initial dose. A gradual increase in dosage may be considered if no clinical improvement is observed. Based on pharmacokinetic parameters, steady-state sertraline plasma levels are achieved after approximately 1 week of once daily dosing; accordingly, dose changes, if necessary, should be made at intervals of at least 1 week. Doses should not exceed a maximum of 200 mg/day.

As with other antidepressants, the full antidepressant effect may be delayed until 4 weeks of treatment or longer.

Sertraline should be administered with food once daily preferably with the evening meal, or, if administration in the morining is desired, with breakfast.

As with many other medications, sertraline should be used with caution in patients with renal and/or hepatic impairment (see Precautions).

Maintenance:
When a satisfactory clinical response has been obtained, the dosage should be reduced (within the 50 to 200 mg range) to the minimum that will maintain relief of symptoms.

Supplied

50 mg:
Each white and yellow capsule contains: Sertraline HCl 50 mg. Nonmedicinal ingredients: Cornstarch; lactose, anhydrous; magnesium stearate; sodium lauryl sulfate. Capsule shells contain gelatin, silicon dioxide, sodium lauryl sulfate, methyl and propylparabens, titanium dioxide, dye D & C Yellow #10, and dye FD & C Yellow #6. Tartrazine-free. White high density polyethylene botles of 100 and 250.

100 mg:
Each orange capsule contains: Sertraline HCl 100 mg. Nonmedicinal ingredients: Cornstarch; lactose, anhydrous; magnesium stearate; sodium lauryl sulfate. Capsule shells contain gelatin, silicon dioxide, sodium lauryl sulfate, methyl- and propylparabens, titanium dioxide, dye D&C Yellow #10 and dye FD&C Red #40. Tartrazine-free. White high density polyethylene bottles of 100.

Store at controlled room temperature between 15 and 30°C.